所有糖皮质激素均与VTE风险增加相关

4月1日《美国医学会杂志-内科学》在线发表的一项报告显示，使用各种糖皮质激素类药物均与静脉血栓栓塞(VTE)风险增加2~3倍相关，风险增加程度取决于糖皮质激素的类型、给药途径和其他因素[JAMA Intern. Med. 2013 April 1 (doi:10.1001/jamainternmed.2013.122)]。

丹麦奥尔胡斯大学医院的Sigrun A. Johannesdottir及其同事报告称，与吸入型糖皮质激素或作用于肠道的糖皮质激素相比，全身糖皮质激素与最高VTE风险相关；与持续或既往使用相比，新使用糖皮质激素与更高VTE风险相关。此外，VTE风险还随糖皮质激素剂量而增加。

上述结果来自一项基于人群的病例对照研究。该研究未能证实该相关性的因果关系，也难以从统计学上解释患者潜在疾病(患者最初服药原因)所产生的混杂影响，因为这些疾病可直接增加VTE风险或使患者活动减少进而导致VTE。但研究者称，不良反应发生的时序、与各种类型糖皮质激素关联强度以及校正多个混杂因素后仍然存在关联的事实，均增加了我们对上述结果反映了真实生物学效应的信心。

研究者利用多个丹麦国家医疗登记库资料，确认了在2005~2012年确诊为VTE的所有成人患者、在研究期间开具了糖皮质激素的所有患者以及所开糖皮质激素所有适应证和所有相关共病情况，并与年龄和性别相匹配的普通人群进行对照分析。共计纳入38,765例VTE病例和387,650例对照者，中位年龄67岁，女性略多于半数。

结果显示，与未使用者相比，所有使用糖皮质激素患者的VTE风险均有所增加，尤其是肺部血栓栓塞风险。

倍他米松、甲基泼尼松龙、泼尼松龙、泼尼松、曲安奈德以及氢化可的松等全身糖皮质激素增加VTE风险的程度最大(在本项研究中没有患者使用地塞米松)，吸入型糖皮质激素和作用于肠道的糖皮质激素也显著增加VTE风险。在全身糖皮质激素类药物中，泼尼松龙和泼尼松增加VTE风险的程度最大。

糖皮质激素新使用者与VTE风险程度最高相关，但目前使用者、持续使用者以及既往使用者风险增加也都很明显。口服制剂与VTE风险增加程度最高相关，但注射剂也显著增加VTE风险。值得一提的是，全身糖皮质激素新使用者VTE风险最高，与未使用者相比，预计发病率比为3.06。VTE风险还随糖皮质激素累积剂量增加而提高。

进一步分析显示，各亚组VTE风险均有所增加。针对服用糖皮质激素类药物至少为5年患者的敏感性分析显示，上述结果未见明显变化。

研究者指出，上述关联的时序性(例如，初始治疗作用最强以及停药后作用消失)与凝血作用相一致。

该研究由奥尔胡斯大学医院临床流行病学研究基金资助，研究者无利益冲突披露。

随刊述评：应警惕VTE

《美国医学会杂志-内科学》副主编Mitchell H. Katz博士指出，该研究提供了糖皮质激素与VTE风险增加相关的有力证据，但这一相关性难以证实究竟是由于接受该类药物治疗的疾病本身导致VTE，还是疾病导致患者活动减少而引发VTE[JAMA Intern. Med. 2013 April 1 (doi:10.1001/jamainternmed.2013.93)]。

上述结果虽不能改变目前糖皮质激素的适应证，但“提醒我们应始终确保接受糖皮质激素治疗患者的潜在受益大于风险，并应做好诊断和治疗血栓栓塞的准备”。

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By: MARY ANN MOON, Cardiology News Digital Network

Use of all glucocorticoids is associated with a two- to threefold increased risk of venous thromboembolism, depending on the type of glucocorticoid, the route of administration, and other factors, according to a report published online April 1 in JAMA Internal Medicine.

Systemic glucocorticoids, as compared with inhaled ones or glucocorticoids that act on the intestines, were associated with the highest risk of VTE. New use was linked to higher risk than continuing or past use, and the VTE risk increased as the dose of glucocorticoids increased, said Sigrun A. Johannesdottir of the department of clinical epidemiology, Aarhus (the Netherlands) University Hospital, and her associates.

These findings are from a population-based case-control study, which cannot prove a cause-and-effect relationship. Moreover, it is difficult to statistically account for all the confounding effects of patients’ underlying disease – the reason they were taking glucocorticoids in the first place – because such disorders raise the risk of VTE directly or cause immobility that in turn can lead to VTE.

However, the timing of this adverse effect, the strength of the association across all types of glucocorticoids, and the fact that the association persisted after the data were adjusted to account for multiple confounders all "increase our confidence that the results reflect a true biological effect," the investigators said.

"Clinicians should be aware of this association," they noted.

Ms. Johannesdottir and her colleagues used data from several Danish national medical registries to identify all adults who were diagnosed with VTE in Denmark in 2005-2012, all patients who filled prescriptions for glucocorticoids during the study period, and all indications for the drugs as well as all relevant comorbidities. They matched 10 control subjects for age and sex from the general population to each study subject.

A total of 38,765 VTE cases and 387,650 controls were included in this study. The median age was 67 years, and slightly more than half of those studied were women.

All glucocorticoid users were found to be at increased risk for VTE, particularly for pulmonary embolism, compared with nonusers, the researchers said.

Systemic glucocorticoids, including betamethasone, methylprednisolone, prednisolone, prednisone, triamcinolone, and hydrocortisone, raised VTE risk to the highest degree. (No patients filled prescriptions for dexamethasone in this study.)

Inhaled corticosteroids and corticosteroids that act on the intestines also raised VTE risk significantly. Among the systemic glucocorticoids, prednisolone and prednisone raised VTE risk the most.

New use of glucocorticoids was associated with the highest risk of VTE, but current use, continuing use, and former use also raised the risk significantly. Oral formulations were associated with the highest risk of VTE, but injectable formulations also raised the risk significantly, Ms. Johannesdottir and her associates reported (JAMA Intern. Med. 2013 April 1 [doi:10.1001/jamainternmed.2013.122]).

In particular, new use of systemic glucocorticoids was associated with the highest risk for VTE, with an estimated incidence rate ratio of 3.06, compared with nonuse of glucocorticoids.

The risk of VTE also rose with increasing cumulative doses of all glucocorticoids.

In further analyses, elevated risk for VTE persisted across all the subgroups that were examined.

The findings did not change appreciably in a sensitivity analysis that included only subjects who took glucocorticoids for at least 5 years.

"The temporality of the association (i.e., the strongest effect at initiation of therapy and the absence of an effect after discontinuation) is in line with an effect on coagulation," Ms. Johannesdottir and her associates said.
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This study was supported by the Clinical Epidemiological Research Foundation at Aarhus University Hospital. No relevant conflicts of interest were reported.

View on the News: Be alert to VTE

This study provides strong evidence that glucocorticoids are linked to elevated risk of VTE, an association that is difficult to prove because some of the illnesses that are treated with these drugs may themselves cause VTE or may cause immobility that predisposes patients to VTE, said Dr. Mitchell H. Katz.

The findings don’t change the indications for prescribing glucocorticoids, but they "should remind us to always make sure that the potential benefits of treatment outweigh the risks, and to be prepared to diagnose and treat thromboembolism" in patients taking glucocorticoids, he said.

Dr. Mitchell H. Katz is a deputy editor of JAMA Internal Medicine. His remarks were taken from his editorial accompanying Ms. Johannesdottir’s report (JAMA Intern. Med. 2013 April 1 [doi:10.1001/jamainternmed.2013.93]).